The link between type 2 diabetes mellitus (T2D), an established risk factor for chronic periodontitis (PD), and periodontitis is centered on loss of inflammation regulation. Increasing evidence suggests that both conditions are characterized by altered innate immune responses and overproduction of pro-inflammatory signals. As a master regulator of inflammation, the macrophage (M?) acts to limit pathological changes or to elevate the response to the next level: adaptive immunity. The M? role in chronic inflammation is known to becritical for onset of insulin resistance in T2D and bone loss in PD. Temporal and spatial imbalances in M? phenotypic polarization to a pro- (M1) or anti-inflammatory (M2) phenotype may be responsible for chronicity and resolution failure in PD. The major cellular source of gingival pro-inflammatory cytokines, particularly interleukin-1 beta, interleukin-8 and tumor necrosis factor alpha, in severe to advanced PD, is the M?. By contrast, the M2 M?-derived anti- inflammatory cytokine interleukin-10, although widely expressed in inflamed periodontal tissues, is associated with decreased severity of PD. Nonetheless, the concentration of interleukin-4 was found to decrease in the gingival crevicular fluid of patients with PD compared with controls. Similarly, M1 polarization of adipose tissue M? has been proposed as one mechanism for onset of insulin resistance in T2D whereas M2 polarization appears to be protective against insulin resistance. Two different circulating monocyte (Mo) populations, with distinct surface chemokine receptor profiles common to primates and rodents, CCR2highCX3CR1low and CCR2lowCX3CR1high, seem to share M1 and M2 phenotypes (as defined in mice), respectively, indicating different M1/M2 recruiting mechanisms at sites of inflammation. Therefore, M? polarization to either predominantly M1 or M2 phenotype represents an essential target for monitoring disease activity, modulating immune responses to pathogens in patients at risk for developing PD and increasing insulin sensitivity in patients with T2D. Restoration of tissue homeostasis involves an active inflammation resolution process for which M? polarization switching is central. Endogenous lipids including lipoxins and resolvins mediate the resolution process. Using mice that are transgenic over-expressers or knockout for the resolvin E1 receptor, we will test the hypothesis that resolvin E1 through its receptor ERV1 can modulate circulating Mo precursors of M? to actively resolve un-regulated inflammation associated with T2D and PD.